Cutaneous scars are areas of fibrous tissue, or fibrosis, that replaces normal skin following injury. Scars result from the biological wound repair processes of the body. After an injury, a clot or provisional wound matrix forms. Specialized cells called fibroblasts migrate to the provisional wound matrix and act to close the wound. This is accomplished by the production of extracellular collagen by fibroblasts. Although the collagen composition of scar tissue is similar to the tissue that it replaces, the collagen fibers of scar tissue are often variably expressed and are organized and cross-linked in a parallel direction rather than the “basket weave” orientation of normal skin tissue. Additionally, cutaneous scar tissue does not contain the adnexal structures such as hair follicles, sebaceous glands and sweat glands that are present in normal skin.
Due to the variable expression or over-expression of collagen by fibroblasts, cutaneous scars can assume different phenotypes. These include atrophic (or hypotrophic) scars, hypertrophic scars and keloids.
Atrophic scars have the appearance of depressions or recesses that lie below the surface of the surrounding skin (aka “sunken scarring”). They occur when underlying structures such as fat or muscle, are lost due to injury along with insufficient production of new collagen fibers at the base of the scar. Atrophic scarring is commonly associated with acne, infection (eg: Varicella zoster or Stapphylococcus), surgery or accidental trauma. Atrophic scars often appear red because of dermal thinning and increased visibility of the underlying capillary network.
Hypertrophic scarring occurs when fibroblasts over-produce collagen during the healing process. This causes the scar to be raised above the surrounding skin. Hypertrophic cutaneous scars are common following surgical wound closure or traumatic skin injuries.
Keloids are considered to be a more severe form of hypertrophic scarring. Keloids continue to grow into large, benign neoplasms. Keloids are more common in dark-skinned people. They can occur following surgery, trauma, acne or body piercing. They tend to occur on the shoulders and chest and are more common in wounds closed by granulation tissue, a.k.a. second intention. The remainder of this description will be limited to the discussion of atrophic type of cutaneous scar and its treatment.
Because patients with atrophic cutaneous scarring seek to improve the appearance and texture of their skin, treatments have been developed to address this issue. The clinical objective behind treating atrophic scarring is to physically raise the depressed area of scarring to the same physical level as the surrounding skin, therefore allowing a smoother transition between the scar and the normal skin. Treatments that are currently in use include injectable soft tissue fillers, collagen induction therapy, chemical reconstruction of skin scars (CROSS) therapy, laser treatment and transplantation of autologous fibroblasts.
Injectable dermal fillers are substances that are injected into the depressed areas of atrophic scars. The currently approved substances used as fillers consist of collagen, hyaluronic acid, poly-L-lactic acid, polymethylmethacrylate with bovine collagen, calcium hydroxylapatite or autologous fibroblasts. Although injections of these substances result in cosmetic improvement of atrophic scars, the effect is temporary and patients require repeat injections over time. Additional side effects of fillers include uneven skin contour and allergic reactions.
The principle underlying collagen induction therapy is to stimulate fibroblasts at the base of the atrophic scar to produce collagen in an attempt to fill the recessed area. Collagen induction therapy utilizes the technique of microneedling, often administered via microneedle rollers applied directly to the scar. This treatment produces small punctures in the skin that act to stimulate fibroblasts to produce collagen in response to the trauma. The collagen will then act to thicken the bed of the scar, raising it to the level of the surrounding normal skin. Collagen induction therapy has been met with varying amounts of success. Aside from pain during the procedure, risks include infection and bleeding. Additionally, multiple treatments are typically required.
Chemical reconstruction of skin scars (CROSS) therapy consists of applying full concentration trichloroacetic acid to atrophic scars. The acid produces a localized cutaneous chemical injury. Similar to collagen induction therapy, CROSS therapy attempts to use targeted injury to stimulate fibroblasts to increase collagen production in the injured areas. Risks include infection and multiple treatments are typically required.
Ablative laser treatment with a carbon dioxide or Er:YAG laser is also used to treat atrophic cutaneous scars. The principle behind laser treatment is to smooth the transition between the depressed borders of atrophic scars and the normal surrounding skin. This serves to make the scarred skin areas appear less noticeable. The laser can also be used to treat the bed of the atrophic scar. The rationale is that laser injury will stimulate fibroblasts to produce collagen that will then fill in the damaged areas. Unfortunately, laser treatment is painful, requires multiple treatments and can be very costly.
There is currently no available medical therapy for treating atrophic cutaneous scars that does not involve localized, trauma-induced stimulation of collagen production by fibroblasts. The present disclosure describes methods and compositions for treating atrophic cutaneous scars in humans via stimulation of fibroblast collagen production using the topical application of PGF 2α analogs admixed in a pharmaceutically suitable vehicle.